Many genes, when mutated, can disrupt the hearing process. Because there are many genes causing deafness, it is important to enroll large families with sufficient power for linkage detection. Under the current protocol, deafness loci segregating among consanguineous families from Pakistan, India and Iran are being ascertained. Most families consist of at least three deaf siblings or two deaf first cousins. These types of families have simulated LOD scores above 2. Hereditary deafness in some of these families map to known loci such as DFNB1, DFNB3, DFNB4, DFNB6, DFNB7/DFNB11, DFNB8/DFNB10, DFNB9, DFNB12, DFNB18, DFNB21, DFNB23, DFNB26, DFNB28, DFNB29, USH1D, USH1F and USH2B. The hearing loss in other families are unlinked to the known deafness loci. This year we have mapped several new deafness loci and have identified two novel genes involved in hereditary deafness. DFNB29 (located on chromosome 21q22) co-segregates with deafness in two large consanguineous families from Pakistan. The refined linkage interval includes the gene encoding claudin-14, which was found to be mutated in both families. Claudin-14, a member of the mammalian tight junction family of proteins, is expressed in the liver, kidney and inner ear. DFNB26 (located on chromosome 4q31) and its modifier, DFNM1 (located on chromosome 1q23), were mapped in one very large consanguineous family from Pakistan. DFNM1 is the first deafness modifier gene to be mapped. This dominant modifier protects family members from recessive DFNB26 hearing impairment. Work is underway to identify these two genes and determine function in the auditory system. Mutations of PCDH15 encoding protocadherin 15 were identified as the cause of Usher syndrome type 1F. Individuals with Usher syndrome type 1 are usually born with severe hearing impairment, vestibular areflexia and retinitis pigmentosa. The onset of blindness is usually around puberty. Mutations in this gene were found in 2 different families from Pakistan.